Development of an Efficient and Practical Route for the Multikilogram Manufacture of Ethyl 5-Cyano-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate and Ethyl 6-Chloro-5-cyano-2-methylnicotinate, Key Intermediates in the Preparation of P2Y12 Antagonists

Elucidation of the mechanism of formation of two major impurities in the synthetic route towards key intermediate ethyl 5-cyano-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate 1, led directly to the development of a route with significant process improvements in terms of yield, purity, and operability. The overall process yield increased from 15% to 73% without the need for extra purification steps, giving the key intermediate ethyl 6-chloro-5-cyano-2-methylnicotinate, 2, in excess of 80 kg to support clinical development.